Fatigue in Alzheimer's disease: biological basis and clinical management-a narrative review.

BACKGROUND: Fatigue is a common symptom in neurodegenerative diseases and is associated with decreased cognitive performances. A full knowledge of the causes and physiopathological pathways leading to fatigue in Alzheimer's disease could help treating this symptom and obtain positive effects on cognitive functions. OBJECTIVES: To provide an overview of the clinical conditions and the biological mechanisms leading to fatigue in Alzheimer's disease patients. To review the recent advances on fatigue management and describe the landscape of future possibilities. METHODS: We performed a narrative review including all type of studies (e.g. cross-sectional and longitudinal analysis, reviews, clinical trials). RESULTS: We found very few studies considering the symptom fatigue in Alzheimer's disease patients. Populations, designs, and objectives varied across studies rendering comparability across studies difficult to perform. Results from cross-sectional and longitudinal analysis suggest that the amyloid cascade may be involved in the pathogenesis of fatigue and that fatigue may be a prodromal manifestation of Alzheimer's disease. Fatigue and neurodegeneration of Alzheimer's disease could share common brain signatures (i.e. hippocampal atrophy and periventricular leukoaraiosis). Some mechanisms of aging (i.e. inflammation, mitochondrial dysfunction, telomere shortening) may be proposed to play a common underlying role in Alzheimer's disease neurodegeneration and muscle fatigability. Considering treatments, donepezil has been found to reduce cognitive fatigue in a 6-week randomized controlled study. Fatigue is frequently reported as an adverse event in patients treated by anti-amyloid agents in clinical trials. CONCLUSION: The literature is actually inconclusive about the main causes of fatigue in Alzheimer's disease individuals and its potential treatments. Further research is needed to disentangle the role of several components such as comorbidities, depressive symptoms, iatrogenic factors, physical decline and neurodegeneration itself. Given the clinical relevance of this symptom, it seems to be important to systematically assess fatigue by validated tools in Alzheimer's disease clinical trials.

Cognitive decline as an outcome and marker of progression toward dementia, in early preventive trials.

INTRODUCTION: Recent Food and Drug Administration guidance endorses cognitive assessment as a possible primary endpoint for early trials for Alzheimer's disease but emphasizes the need for certainty regarding the relationship with progression to dementia. METHODS: We compared the validity of the 2-year change (Y0-Y2) of 11 markers of neuropsychological and functional abilities for the prediction of incident dementia over the following 3 years (Y2-Y5), in 860 subjects aged 70 years or older, who consulted for memory loss and were included in the "GuidAge" prevention trial. RESULTS: The Free and Cued Selective Reminding Test-Free Recall (FCSRT-FR) score showed the most predictive 2-year change (area under the curve = 0.72 95% confidence interval = 0.64;0.81). Changes in other subscores of the FCSRT, verbal fluencies tasks, and composite cognitive score were also significantly predictive. Conversely, 2-year change of Mini-Mental State Examination, Trail Making test (TMT)-A, TMT-B, Clinical Dementia Rating Sum of Boxes, and Instrumental Activities of Daily Living scores did not significantly predict occurrence of dementia. CONCLUSION: The FCSRT, the Fluency Task, and the composite cognitive score appear to be good cognitive markers of progression toward dementia in early prevention trials.

Biomarker counseling, disclosure of diagnosis and follow-up in patients with mild cognitive impairment: A European Alzheimer's disease consortium survey.

OBJECTIVES: Mild cognitive impairment (MCI) is associated with an increased risk of further cognitive decline, partly depending on demographics and biomarker status. The aim of the present study was to survey the clinical practices of physicians in terms of biomarker counseling, management, and follow-up in European expert centers diagnosing patients with MCI. METHODS: An online email survey was distributed to physicians affiliated with European Alzheimer's disease Consortium centers (Northern Europe: 10 centers; Eastern and Central Europe: 9 centers; and Southern Europe: 15 centers) with questions on attitudes toward biomarkers and biomarker counseling in MCI and dementia. This included postbiomarker counseling and the process of diagnostic disclosure of MCI, as well as treatment and follow-up in MCI. RESULTS: The response rate for the survey was 80.9% (34 of 42 centers) across 20 countries. A large majority of physicians had access to biomarkers and found them useful. Pre- and postbiomarker counseling varied across centers, as did practices for referral to support groups and advice on preventive strategies. Less than half reported discussing driving and advance care planning with patients with MCI. CONCLUSIONS: The variability in clinical practices across centers calls for better biomarker counseling and better training to improve communication skills. Future initiatives should address the importance of communicating preventive strategies and advance planning.

Potentially modifiable factors associated with agitation and aggression in Alzheimer's disease: results of the ICTUS study.

OBJECTIVES: To study potentially modifiable factors associated with the severity of agitation or aggression (A/A) symptoms among Alzheimer's disease (AD) patients. DESIGN: Data from the Impact of Cholinergic Treatment Use (ICTUS) study, European longitudinal prospective observational study. SETTING: Community dwelling outpatients included in 29 European memory clinics. PARTICIPANTS: 1375 participants with probable AD (Mini-Mental State Examination score of 10-26) with an informal caregiver. MEASUREMENTS: At baseline and twice yearly over the two-year follow-up, patients underwent comprehensive clinical and neuropsychological assessments: sociodemographic data, cognitive status, functional impairment, and assessment of neuropsychiatric symptoms based on Neuro-Psychiatric Inventory (NPI). The ZARIT scale assessed the caregiver's burden. The variable of interest was the severity of the item of A/A of the NPI. To study factors associated to the severity of A/A symptoms six months later, a multivariate mixed regression model was used. RESULTS: Frequency of A/A symptom varied from 30% to 34% at each visit. Two factors were found to be independently associated with the severity of A/A: (1) the presence of affective disorder (anxiety, depression, and/or irritability) that increased the severity of the A/A by 0.89 point (coefficient:0.89; 95% Confidence Interval (CI) = [0.48,1.30], p < 0.001), and (2) a severe caregiver burden that increased the severity of the A/A by 1.08 point (coefficient:1.08; 95% CI = [0.69,1.47], p < 0.001). CONCLUSION: Research should evaluate whether the identification and treatment of an affective disorder along with the evaluation and optimal management of the caregiver would have a positive impact on the course of A/A in mild to moderate AD patients.

Duration of preclinical, prodromal, and dementia stages of Alzheimer's disease in relation to age, sex, and APOE genotype.

INTRODUCTION: We estimated the age-specific duration of the preclinical, prodromal, and dementia stages of Alzheimer's disease (AD) and the influence of sex, setting, apolipoprotein E (APOE) genotype, and cerebrospinal fluid tau on disease duration. METHODS: We performed multistate modeling in a combined sample of 6 cohorts (n = 3268) with death as the end stage and estimated the preclinical, prodromal, and dementia stage duration. RESULTS: The overall AD duration varied between 24 years (age 60) and 15 years (age 80). For individuals presenting with preclinical AD, age 70, the estimated preclinical AD duration was 10 years, prodromal AD 4 years, and dementia 6 years. Male sex, clinical setting, APOE ε4 allele carriership, and abnormal cerebrospinal fluid tau were associated with a shorter duration, and these effects depended on disease stage. DISCUSSION: Estimates of AD disease duration become more accurate if age, sex, setting, APOE, and cerebrospinal fluid tau are taken into account. This will be relevant for clinical practice and trial design.

European Prevention of Alzheimer's Dementia Registry: Recruitment and prescreening approach for a longitudinal cohort and prevention trials.

INTRODUCTION: It is a challenge to find participants for Alzheimer's disease (AD) prevention trials within a short period of time. The European Prevention of Alzheimer's Dementia Registry (EPAD) aims to facilitate recruitment by preselecting subjects from ongoing cohort studies. This article introduces this novel approach. METHODS: A virtual registry, with access to risk factors and biomarkers for AD through minimal data sets of ongoing cohort studies, was set up. RESULTS: To date, ten cohorts have been included in the EPAD. Around 2500 participants have been selected, using variables associated with the risk for AD. Of these, 15% were already recruited in the EPAD longitudinal cohort study, which serves as a trial readiness cohort. DISCUSSION: This study demonstrates that a virtual registry can be used for the preselection of participants for AD studies.

Evaluating the clinical relevance of a cognitive composite outcome measure: An analysis of 1414 participants from the 5-year GuidAge Alzheimer's prevention trial.

INTRODUCTION: Composite cognitive scores have been developed as primary outcome measures for preclinical/prevention trials for Alzheimer's disease (AD), mainly using observational data and with little consideration of clinical relevance. METHODS: Secondary analysis of placebo group data from a 5-year AD prevention trial. The composite score was the average of the following z scores: MMSE orientation items, Free and Cued Selective Reminding Test, Category Fluency, Trail Making Test-part B. RESULTS: Composite score change from baseline differed significantly by age, APOE genotype, and CDR progression and AD dementia status. A 1 point decrease in baseline score was highly predictive of 5-year AD dementia risk (HR = 3.51, 95% CI, 2.62-4.71, P < .001). The 1 year minimum clinically important difference was estimated at -0.3 points and predicted AD dementia. DISCUSSION: We explored the clinical relevance of a composite score in a prevention trial setting. This type of analysis facilitates the interpretation of composite scores and informs power calculations.

An Analysis of the Public Financial Support Eligibility Rule for French Dependent Elders with Alzheimer's Disease.

BACKGROUND: It is crucial to define health policies that target patients with the highest needs. In France, public financial support is provided to dependent patients: it can be used to finance informal care time and nonmedical care use. Eligibility for public subsidies and reimbursement of costs is associated with a specific tool: the autonomie gérontologie groupes iso-ressources (AGGIR) scale score. OBJECTIVE: Our objective was to explore whether patients with Alzheimer's disease who are eligible for public financial support have greater needs than do noneligible patients. METHODS: Using data from the Dépendance des patients atteints de la maladie d'Alzheimer en France study, we calculated nonmedical care expenditures (in €) using microcosting methods and informal care time demand (hours/month) using the Resource Use in Dementia questionnaire. We measured the burden associated with informal care provision with Zarit Burden Interview. We used a modified two-part model to explore the correlation between public financial support eligibility and these three variables. RESULTS: We find evidence of higher informal care use, higher informal caregivers' burden, and higher care expenditures when patients have an AGGIR scale score corresponding to public financial support eligibility. CONCLUSIONS: The AGGIR scale is useful to target patients with the highest costs and needs. Given our results, public subsidies could be used to further sustain informal caregivers networks by financing programs dedicated to lowering informal caregivers' burden.

Donepezil decreases annual rate of hippocampal atrophy in suspected prodromal Alzheimer's disease.

INTRODUCTION: The purpose of this study was to study the effect of donepezil on the rate of hippocampal atrophy in prodromal Alzheimer's disease (AD). METHODS: A double-blind, randomized, placebo-controlled parallel group design using donepezil (10 mg/day) in subjects with suspected prodromal AD. Subjects underwent two brain magnetic resonance imaging scans (baseline and final visit). The primary efficacy outcome was the annualized percentage change (APC) of total hippocampal volume (left + right) measured by an automated segmentation method. RESULTS: Two-hundred and sixteen only subjects were randomized across 28 French expert clinical sites. In the per protocol population (placebo = 92 and donepezil = 82), the donepezil group exhibited a significant reduced rate of hippocampal atrophy (APC = -1.89%) compared with the placebo group (APC = -3.47%), P < .001. There was no significant difference in neuropsychological performance between treatment groups. DISCUSSION: A 45% reduction of rate of hippocampal atrophy was observed in prodromal AD following 1 year of treatment with donepezil compared with placebo.

Medication development for agitation and aggression in Alzheimer disease: review and discussion of recent randomized clinical trial design.

ABSTRACT Background: The management of disruptive neuropsychiatric symptom (NPS) such as agitation and aggression (A/A) is a major priority in caring for people with Alzheimer's disease (AD). Few effective pharmacological or non-pharmacological options are available. Results of randomized clinical trials (RCTs) of drugs for A/A have been disappointing. This may result from the absence of biological efficacy for medications tested in treating A/A. It may also be related to methodological issues such as the choice of outcomes. The aim of this review was to highlight key methodological issues pertaining to RCTs of current and emerging medications for the treatment of A/A in AD. Methods: We searched PubMed/Medline, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov for RCTs comparing medications with either placebo or other drugs in the treatment of A/A in AD, between January 2008 and December 2013. Results: We identified a total of 18 RCTs; of these, 11 were completed and 7 ongoing. Of the ongoing RCTs, only one is in Phase III. Seven of 10 completed RCTs with reported results did not report greater benefit from drug than placebo. Each of the completed RCTs used a different definition of "clinically significant A/A." There was considerable heterogeneity in study design. The primary endpoints were largely proxy-based but a variety of scales were used. The definition of caregiver and scales used to assess caregiver outcomes were similarly heterogeneous. Placebo response was notable in all trials. Conclusions: This review highlights a great heterogeneity in RCTs design of drugs for A/A in AD and some key methodological issues such as definition of A/A, choice of outcome measures and caregiver participation that could be addressed by an expert consensus to optimize future trials design.